Epstein Barr virus (EBV) is the cause of infectious mononucleosis and is associated with a number of cancers including lymphomas in transplant recipients. We have been studying EBV DNA in the blood of transplant recipients or other immunocompromised persons, patients with chronic active EBV disease, and patients with diseases in which EBV may be a cofactor. [unreadable] [unreadable] Infection with EBV results in lifelong infection of B lymphocytes in the blood with episodic shedding of virus from the throat. The role that virus infection in the throat plays in establishing lifelong infection is controversial. Some studies suggest that EBV in the blood is required for the virus to persist in the body; other studies imply that infection of B cells in the tissues or infection of epithelial cells in the throat may be required for persistent infection. [unreadable] [unreadable] We monitored patients treated with an antibody directed against B lymphocytes (rituximab) and found that several had no detectable B lymphocytes or EBV in the blood. However, these patients continued to shed EBV from the throat. Several models postulate that EBV traffics from the B cells in the blood to the throat where the virus is subsequently shed. While we cannot be certain that B cells infected with EBV may have persisted in the tissues, our findings indicate that EBV in B cells circulating in the bloodstram is not necessary for the virus to persist in, and to be shed from, the oropharynx.[unreadable] [unreadable] EBV has been suspected to have a role in the pathogenesis of rheumatoid arthritis (RA). Patients with RA have higher titers of EBV-specific antibodies and have different cellular (lymphocyte) responses to EBV than healthy persons. Patients with RA also have higher levels of EBV-infected lymphocytes in their blood than healthy persons. Infection with EBV has been postulated to be a trigger for development of rheumatoid arthritis. We measured EBV-specific lymphocyte responses and EBV DNA copies in the blood of patients with RA and in matched healthy controls. Patients with RA showed increased and broadened EBV-specific antibody responses and 7-fold higher levels of EBV DNA copies in their blood compared with controls. In addition, the frequency of one type of lymphocyte in the blood (CD8 T cell) specific for EBV was increased and correlated with the number of copies of EBV DNA copies in the blood, while the frequency of another type of lymphocyte in the blood (CD4 T cell) specific for EBV was not increased. Taken together these results indicate that control of EBV infection is altered in patients with RA and suggest that the increase in EBV-specific lymphocytes and antibodies in these patients is driven by elevated EBV DNA copies in their blood.